Parkinson's disease (PD) is a progressive degenerative disease of the central nervous system (CNS). PD is characterized by muscle rigidity, tremors, a slowness of physical movement (bradykinesia), impaired balance and coordination, and, in advanced stages, a loss of physical movement (akinesia). Over one million Americans suffer from Parkinson's disease, with the prevalence of approximately 1 in 272 or 0.37% in the United States (US Census Bureau, Population Estimates, 2004).
There is no known cure for PD. Patients are treated with drugs and physical therapy to control the symptoms, but the disease is a progressive disorder and symptoms continue to worsen throughout life. Four major classes of drugs are used to treat PD: Levodopa, direct dopamine agonists, catechol-O-methyltransferase (COMT) inhibitors and anticholinergics. Other types of drugs include selegiline (an MAO-B inhibitor), amantadine (an antiviral agent), vitamin E and hormone replacement therapy. Although these treatments may provide relief from the symptoms of PD, these noncurative drug treatments are often are accompanied by side effects, such as low blood pressure, nausea, constipation, and various psychiatric or behavioral disorders (e.g., hallucinations, depression, and sleep disorders).
While the molecular bases for PD have not been fully elucidated, several genetic regions have been found to be associated with PD. The PARK1 region at 4q21 contains the alpha-synuclein (SNCA) gene. Certain mutations in this gene confer a rare autosomal dominant form of PD (Duvoisin, R. C. (1996), Recent advances in the genetics of Parkinson's disease, Adv Neurol 69:33-40; Polymeropoulos et al. (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson's disease, Science 276:2045-7; and Kruger et al. (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease, Nat Genet. 18:106-108). The PARK2 region at 6q25-27 contains the Parkin gene. The loss of function of both copies of the parkin gene confers an autosomal recessive juvenile form of PD (Abbas et al. (1999) A wide variety of mutation in the parkin gene are responsible for autosomal recessive parkinsonism in Europe, Hum Mol Genet. 8:567-574; Lucking et al. (1998) Homozygous deletions in the parkin gene in European and North African families with autosomal recessive juvenile parkinsonism, Lancet 352:1355-1356; and Lucking et al. (2000) Association between early-onset Parkinson's disease and mutations in the parkin gene, N Engl J Med 342:1560-1567). Other regions believed to contain one or more genes associated with PD include PARK3 at 2p13 (autosomal dominant), PARK4 at 4p15 (autosomal dominant; same locus as PARK1), PARK5 at 4p14 (which contains a gene encoding a neuron-specific C-terminal ubiquitin hydrolase), PARK6 at 1p35 (autosomal recessive), PARK7 at 1p36 (which contains the DJ-1 gene; autosomal recessive) and PARK8 at 12p1.2-q13.1 (which contains the LRRK2 gene; autosomal dominant). Additional loci designated PARK9, PARK10, PARK11, PARK12, PARK13, PARK14, PARK15, and PARK16 have also been linked to PD. While the molecular bases for most cases of PD are unclear, the various genetic regions that have been linked to this disease serve to illustrate the potential that the etiology of PD may involve the interaction of a large number of genetic components.